Even now, parasitic protozoan infections are widely known mainly around tropical or subtropical regions, and can be exemplified by malaria, leishmaniasis, African trypanosomiasis (African sleeping sickness), American trypanosomiasis (Chags disease), lymphatic filariasis, babesiosis, cryptosporidiosis and toxoplasmosis. These infections can be classified into those infecting only humans, and parasitic zoonosis also infecting domestic animals or small animals, both leading to significant economic and social loss.
Among these diseases, there are some diseases which do not have a therapeutic agent showing a sufficient effect, or some diseases which have problems such as emergence and diffusion of drug-resistant protozoa, or side effects of therapeutic agents. Therefore, an effective agent is desired. Further, since these diseases include diseases which cause serious symptoms with which patients cannot have a normal social life, diseases which force patients to be in a bedridden state in which nursing care is necessary, and diseases which lead to development of lethal symptoms, rapid development of a chemotherapeutic agent is an absolute necessity. However, there are no vaccines showing effectiveness against these diseases at present, and their future development is also said to be difficult. Under such circumstances, development of a chemotherapeutic agent which can be taken orally or by injection, or administered in a similar way thereto is strongly desired.
Masataka Ihara, one of the present inventors, and his collaborators have carried out research and development of a medicinal composition for prevention or therapy of a protozoal disease, containing as an active ingredient a phenoxanizium compound (Patent Document 1); and a medicinal composition for prevention or therapy of a protozoal disease, containing as an active ingredient an azarhodacyanine compound (Patent Document 2).
A number of benzo[a]phenoxzines and benzo[a]phenoxazonium compounds 1 which are salts thereof with acids have been synthesized so far, and reported to have antitumor activities (Non-patent Documents 1 to 5). On the other hand, in terms of reported examples of inhibitory activities on the growth of protozoans which cause tropical diseases such as malaria, there are cases wherein R3 in General formula (1) is a hydrogen atom or an ethyl group, but their in vitro and in vivo activities are low (Non-patent Documents 6 and 7).
Patent Document 1: International Publication WO2006/087935
Patent Document 2: International Publication WO2006/137258
Non-patent Document 1: M. L. Crossley, P. F. Dreisbach, C. M. Hofman, R, P. Parker, J. Am. Chem. Soc., 74, 573-578, 1952
Non-patent Document 2: M. L. Crossley, R. J. Turner, C. M. Hofman, P, F. Dreisbach, R. P. Parker, J. Am. Chem. Soc., 74, 578-584, 1952
Non-patent Document 3: M. L. Crossley, C. M. Hofman, P, F. Dreisbach, J. Am. Chem. Soc., 74, 584-586, 1952
Non-patent Document 4: N. Motohashi, Yakugaku Zasshi, 102, 646-650, 1982
Non-patent Document 5: N. Motohashi, Medicinal Research Reviews, 11, 239-294, 1991
Non-patent Document 6: K. Takasu, T. Shimogama, C. Satoh, M. Kaiser, R. Brun, M. Ihara, J. Med. Chem., 50, 2281-2284, 2007
Non-patent Document 7: J. L. Vennerstrom, M. T. Makler, C. K. Angerhofer, J.
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